Therapy-related leukemias following treatment with drugs that target DNA topoisomerase II frequently involve translocations of the MLL gene at chromosome band l 1q23. This research project will focus on functional analysis of MLL translocations, with a major focus on the MLL-CBP translocation. MLL-CBP was cloned as the MLL fusion present in patients with a t(11; 16) (q23 ;p 13). With one exception, these patients had therapy-related leukemia, and a substantial proportion presented with a therapy-related myelodysplastic syndrome. We recently developed murine model systems for the in vitro and in vivo analysis of the MLLCBP fusion. This project proposes studies to further delineate critical functions contributed by CBP to the fusion protein (Aim 1), to determine the functional effects of domain swapping on the leukemic and preleukemic phenotype (Aim 3), and to determine the effects of the MLL-CBP fusion on hematopoietic cell lineage commitment and survival (Aims 2 & 4).